Hepatitis C virus (HCV)-related deaths now exceed HIV-related deaths in the US. Throughout the world, HCV is hyperendemic in people who inject drugs (PWID). New outbreaks of acute HCV infection are unfolding in HIV-positive men who have sex with men (MSM) and in 15-24 year olds who have transitioned from abuse of prescription opioids to illicit opiate injection. In patients with chronic HCV infection, 20-25% wil develop liver disease which may manifest as cirrhosis, liver failure or hepatocellular carcinoma (HCC). The prognosis for HCC is extremely poor, and HCV is the chief etiologic agent for this type of cancer. Recent discoveries in HCV prevention and treatment provide a great opportunity to reverse the trend toward increasing rates of HCV, HCV/HIV co-infection, and HCC. This study will use the methods of Implementation Science - research synthesis, mathematical modeling and simulation, and comparative effectiveness analyses - to determine how best to constitute a portfolio of interventions for the prevention and control of HCV and its consequences while taking into limited resources and underlying epidemiologic and social network features account. A dissemination plan will make extensive use of technology, including social media, and guidance from key stakeholders. These are our specific aims: 1. Synthesize evidence characterizing a) transition from misuse of prescription opioids to drug injection, b) HCV epidemiology and prevention for PWID and HIV+ MSM, and c) progression and treatment of HCV disease in these two groups, to derive best estimates to populate our HCV natural history and transmission models. 2. Use agent-based modeling to estimate the effects of scale-up of individual and combined prevention- and treatment-related interventions on HCV transmission and natural history in PWID and HIV+MSM. 3. Determine the combination of interventions for particular budget and epidemiologic scenarios that a) minimizes acute and chronic HCV infections, including HIV/HCV co-infection, b) prevents the greatest number of cases of HCV-related HCC and other serious sequelae, c) maximizes life expectancy and quality- adjusted life expectancy and d) reduces health disparities. 4. In collaboration with our Dissemination Advisory Board, apply an integrated knowledge-exchange approach to providing our target audiences (policymakers, public health and harm reduction practice communities, PWID and HIV+MSM) with the knowledge and tools to implement evidence-based HCV control strategies or reduce personal risk of infection and its consequences. The broad objective of this study is to provide an evidence base to guide allocation of scarce public resources in the US and other countries where HCV is principally transmitted among PWID. This will be accomplished by synthesizing, modeling and translating very recent developments in HCV epidemiology, prevention and treatment into practical tools to optimize population health.